2,7-dimorpholino-4-tertiaryamino-6-heteroaryl-pteridines



United States Patent Int. Cl. C07d 87/58, 87/46, 51/46 US. Cl. 260-246Claims ABSTRACT OF THE DISCLOSURE The compounds are2,7-dimorpholino-4-amino-6-aromatic heterocyclic-substituted-pteridines,useful as coronary dilators in warm-blooded animals.

This invention relates to novel pteridine derivatives, as well as tovarious methods of preparing these compounds.

More particularly, the present-invention relates to a novel class ofpteridine substitution products of the formula 6 ts/hai \O wherein R andR which may be identical to or different from each other, are loweralkyl, especially methyl,

n and m, which may be identical to or different from each other, areintegers from 0 to 4, inclusive, preferably 0 to 2,

R is lower alkyl, benzyl or hydroxy-substituted lower alkyl,

R, is hydroXy-substituted lower alkyl, and Ar is a 5- to 6-memberedunsaturated aromatic heterocycle attached to the pteridine nucleusthrough a ring carbon atom, especially thienyl, chlorofuryl or pyridyl,or

METHOD A By reacting a pteridine substitution product of the formulawherein Ar, R and R have the same meanings as in formula I, and Z and Zare halogen atoms, substituted hydroxyl groups or substituted mercaptogroups, with a morpholine compound of the formula wherein R R m and nhave the same meanings as in Formula I.

METHOD B By reacting a pteridine substitution product of the formula N Iq I L N N 0 \t/ N N Y wherein R R Ar, n and m have the same meanings asin Formula I, and Z is a halogen atom, a substituted hydroxyl group or asubstituted mercapto group, with a secondary amine of the formulawherein R and R have the same meanings as in Formula I.

The reactions of methods A and B above are most advantageously performedat a temperature between room temperature and 220 C., and in thepresence of an inert organic solvent and an acid-binding agent, ifnecessary. By acid-binding agent we mean a compound capable of tying upor neutralizing the hydrogen halide released by the reaction when Z Z orZ in compounds II and IV above are halogen atoms.

The selection of the most eifective reaction temperature depends largelyupon the nature of substituents Z Z and Z;, in pteridine compounds IIand IV as well as upon the reactivity of the morpholine compound IIIa orIII!) and the secondary amine V. If Z Z and/0r Z are halogen atoms, onlymoderately elevated temperatures are required; on the other hand, if Z Z.and/ or Z;; are substituted hydroxyl groups or substituted mercaptogroups, the reaction will proceed satisfactorily only at substantiallyhigher temperatures. In those instances where the reaction is sluggish,it may also be advantageous to add an accelerator to the reactionmixture, preferably a copper salt or a salt formed by compound IIIa,III]; or V with an acid; the reaction may also be accelerated bycarrying it out in a closed vessel.

Examples of preferred substituents for substituted hydroxyl or mercaptogroups represented by Z Z and Z are lower alkyl, aralkyl or aryl.

Examples of suitable inert organic solvents are acetone, benzene,dioxane and dimethylformamide.

Examples of suitable acid-binding agents are inorganic or tertiaryorganic bases, such as alkali metal hydroxides, alkali metal carbonatesand trialkylamines. However, a stoichiometric excess of the morpholineIIIa or l'lIb or the secondary amine V over and above the amountrequired for reaction with the pteridine derivativ or IV may also serveas the acid-binding agent and/ or the solvent medium.

If the morpholino substituents in the 2- and 7-positions of Formula Iare to be identical, at least two mols of a morpholine compound 1110 orIIIb must be provided per mol of the pteridine compound II in method A.On the other hand, if the morpholino substituents are to be different,they may be introduced in stepwise fashion; thus, if Z and Z inpteridine compound II are identical, for instance, identical halogenatoms, the pteridine compound II is first reacted with one molequivalent of morpholine compound IIIa, and the reaction product is thenreacted with at least one mol equivalent of morpholine compound IIIb. IfZ and 2;, in pteridine compound II are different, for instance, if oneis a halogen atom and the other is a substituted hydroxyl or mercaptogroup, the halogen atom will, as a rule, be replaced first.

The pteridine starting compounds II and IV may be prepared by the methoddescribed in German Patent No. 1,088,969. For instance, a compound ofthe Formula II may be prepared by reacting a corresponding 6-aryl-2,4,7-trichloro-pteridine with a secondary amine V; similarly, a compound ofthe Formula IV may be prepared by reacting a2,7-dichloro-4-alkylmercapto-6-aryl-pteridine with a morpholine compoundIIIa or IIIb.

Accordingly, using the process described in said German patent, thefollowing starting compounds of the Formulas II or IV were prepared:

2,7-dichloro-4-methylethanolamino-6-(p-chlorophenyl)- pteridine, M.P.164-165 C.; 4-ethanolisopropanolamino-2,7-dichloro-6-(m-tolyl)-pteridine, M.P. 165166 C.', 2,7-dichloro-4-diisopropanolamino-6-(p-methoxyphenyl) pteridine, M.P. 152-155 C.;2,7-dichloro-4-diisopropanolamino-6-(p-tolyl)- pteridine, M.P. 183-185C.; 4-ethanolisopropanolaminw2,7-dichloro-6-(o-tolyl)- pteridine, M.P.172174 C.; 4-ethanolisopropanolamino-2,7-dichloro-6- (2-thienyl)pteridine, M.P. 188190 C.; 2,7-dichloro-4-diisopropanolamina-6-2-thienyl) pteridine, M.P. 194196 C.

The following examples will further illustrate the present invention andenable others skilled in the art to understand it more completely. Itshould be understood, however, that the present invention is not limitedto the particular examples given below.

EXAMPLE 1 Preparation of 2,7-dimorpholino-4-methylethanolamino-6-(p-chlorophenyl)-pteridine by method A 0.02 mol of2,7-dichloro-4-methylethanolamino-6-(pchlorophenyl)-pteridine wasadmixed with 25 cc. of morpholine, and the mixture was refluxed forthirty minutes. Thereafter, while the reaction mixture was still hot, itwas poured into about 500 cc. of water, whereby a precipitate formed.The aqueous mixture was allowed to stand at room temperature for sometime, the precipitate was separated by vacuum filtration, and the filtercake Was washed with water and dried. The dry product was dissolved in0.1 N hydrochloric acid and reprecipitated by adding 2 N ammonia to theacid solution. The reprecipitated product was finally recrystallizedfrom methanol. The thus purified reaction product had a melting point of260262 C. It was identified to be4-methylethanolamino-2,7-dimorpholino-6-(p-chlorophenyl)-pteridine ofthe formula I IQ q NAk N 4 EXAMPLE 2 Preparation of2,7-dimorpholino-4-ethylethanolamino-6- (p-nitrophenyl)-pteridine bymethod B 0.005 mol of2,7-dimorpholino-4-ethylthio-6-(p-nitropheny1)-pteridine was admixedwith 20 cc. of ethylethanolamine and a small amount of ethylethanolaminehydrochloride, and the mixture was refluxed for about fifteen hours.Thereafter, the excess unreacted ethylethanolamine was distilled off,and the residue was taken up in about 200 cc. of water. A precipitateformed, which was separated, recrystallized from a 2:1 mixture ofethylene chloride and cyclohexane, dissolved in 0.1 N hydrochloric acidand reprecipitated with 2 N ammonia. The thus purified product had amelting point of 2l4215 C. and was identified to be2,7-dimorpholino-4-ethylethanolamino-6- (p-nitrophenyl)-pteridine of theformula EXAMPLE 3 Using a procedure analogous to that described inExample 1, 2,7dimorpho1ino-4-ethanolisopropanolamino-6-(m-tolyl)-pteridine, M.P. 231233 C., of the formula (CHa-(JH-CHghN wasprepared from 2,7-dichloro-4-diisopropanolamino-6-(p-methoxyphenyl)-pteridine and morpholine.

EXAMPLE 5 Using a procedure analogous to that described in Example 1,2,7 dimorpholino-4-diisopropanolamino-6-(5- chloro-2-furyl)-pteridine,M.P. 208211 C. of the formula OH (CHa-(EH-CHzhN W was prepared from2,7-dichloro-4-diisopropanolamino-6- (5'-chloro-2-furyl)-pteridine andmorpholine.

EXAMPLE 6 110mm C2H4OH N C f -L \N or-s was prepared from2,7-dichloro-4-ethanolpropanolamino- 6-(3-pyridyl)-pteridine andmorpholine.

EXAMPLE 7 Using a procedure analogous to that described in Example 2,2,7 dimorpholino 4 ethylethanolamino-6-(paminophenyl)-pteridine, M.P.225-226" C., of the formula HOH4Cg\ C2H5 NH L so N N was prepared from2,7 dimorpholino 4 ethylthio-6-(paminophenyl)-pteridine andethylethanolamine.

EXAMPLE 8 Using a procedure analogous to that described in Example 1,2,7-dimorpholino 4 diisopropanolamino-6-(p- 4O tolyl)-pteridine, M.P.155-160" C., of the formula on (OH -(JH-CH 1}T /C- Fat N N was preparedfrom 2,7-dichloro-4-diisopropanolamino-6- (p-to1yl) pteridine andmorpholine.

EXAMPLE 9 Using a procedure analogous to that described in Example 1,2,7-dimorpholino-4-ethanolisopropanolamino-6- (o-tolyl)-pteridine, M.P.210-211 C., for the formula 11 CHz- CH-CH: CZHAOH 5* m N N N o wasprepared from 2,7-dichloro 4ethanolisopropanolamino-6-(otoly1)-pteridine and morpholine.

EXAMPLE 10 Using a procedure analogous to that described in Ex- 6 ample1, 2,7-dimorpholino-4-ethanolisopropanolamino-6- (2'-thienyl)-pteridine,M.P. 212214 C., of the formula CHz-CH-CHa 02114011 f/ I I J s l I H o NN N/ N 0 was prepared from 2,7-dichloro 4ethanolisopropanolamino-6-(2-thieny1)-pteridine and morpholine.

EXAMPLE 11 Using a procedure analogous to that described in Example 2,7dimorpholino-4-diisopropanolamino-6-(2'- thienyl)-pteridine, M.P. 180182C., of the formula was prepared from2,7-dichloro-4-diisopropanolamino-6- (2-thienyl)-pteridine andmorpholine.

The compounds according to the present invention, that is, thoseembraced by Formula I above, have useful pharmacodynamic properties.More particularly, they exhibit very effective, long-lasting coronorydilating properties in warm-blooded animals. In addition, the compoundsof the instant invention exhibit hypotensive, spasmolytic and positiveinotropic activities in warm-blooded animals; moreover, they protect theheart against oxygen insufiiciency and suppress thrombocyteagglutination in warm-blooded animals. Their toxicity values are verylow, wherefor their therapeutic ratio is extremely favorable.

For pharmaceutical purposes the compounds of the present invention areadministered to warm-blooded animals perorally or parenterally as activeingredients in customary dosage unit compositions, that is, compositionsin dosage unit form consisting essentially of an inert pharmaceuticalcarrier and one dosage unit of the active ingredient, such as tablets,coated pills, solutions, suspensions, capsules, wafers, suppositoriesand the like. One dosage unit of the compounds of the invention is from1 to 200 mgm., preferably 5 to 100 mgm.

The following examples illustrate a few dosage unit compositionscomprising a compound of the instant invcntion as an active ingredient.The parts are parts by weight unless otherwise specified.

EXAMPLE l2 Hypodermic solution The solution is compounded from thefollowing ingradients:

Distilled water, q.s. ad, 2000.0 by vol.

Compounding procedure: The polyethyleneglycol is admixed with an equalvolume of distilled water, the solu- 0 tion is heated to C., and thetartaric acid and the pteridine compound are dissolved therein. Theresulting solution is cooled to room temperature, diluted with distilledWater to the indicated volume, and filtered until free from suspendedparticles. The filtered solution is filled into white 2 cc.-ampules,which are then sterilized for twenty minutes at 120 C. and sealed. Eachampule contains 10 mgm. of the active ingredient.

EXAMPLE 13 Coated pills The pill core composition is compounded from thefollowing ingredients:

Parts 2,7-dimorpholino-4-diisopropanolamino-6-(p-tolyl)- pteridine 30.0Lactose 30.0 Potato starch 16.5 Polyvinylpyrrolidone 3.0 Magnesiumstearate 0.5

Total 80.0

Compounding procedure: The pteridine compound, the lactose and thepotato starch are intimately admixed with each other, and the mixture ismoistened with an ethanolic 25% solution of the polyvinylpyrrolidone.The moist mass is forced through a 1.5 mm.-mesh screen, and theresulting granulate is dried at 45 C. The dry granulate is again passedthrough the screen and is then thoroughly admixed with the magnesiumstearate. The finished mixture is pressed into 80 mgm.-pill cores, whichare subsequently coated with a thin shell consisting essentially ofsugar and talcum. The coated pills are finally polished with beeswax.Each pill weighs approximately 150 mgm. and contains 30 mgm. of theactive ingredient.

EXAMPLE 14 Tablets The tablet composition is compounded from thefollowing ingredients:

Parts 2,7 dimorpholino 4 diisopropanolamino-6-(ptolyl)-pteridine 60.0Lactose 30.0 Potato starch 23.0 Polyvinylpyrrolidone 6.0 Magnesiumstearate 1.0

Total 120.0

EXAMPLE 15 Gelatin capsules The capsule filler composition is compoundedfrom the following ingredients:

Parts 2,7 dimorpholino 4 diisopropanolamino-6-(ptolyl)-pteridine 50.0Lactose 60.0 Talcum 10.0

Total 120.0

Compounding procedure: The pteridine compound is intimately admixed withthe lactose and the talcum, and 120 mgm.-portions of the mixture arefilled into gelatin capsules of suitable size. Each. capsule contains 50mgm. of the active ingredient.

8 EXAMPLE 16 Drop solution The solution is compounded from the followingingredients:

2,7 dimorpholino 4 diisopropanolamino 6- p-tolyl) -pteridine parts 20.0Tartaric acid do 5.0 Cane sugar do 300.0 Sorbic acid do 1.0 Flavoring do40.0 Ethanol parts by vol. 200.0 Polyethyleneglycol 600 do 200.0

Demineralized water, q.s. ad., 1000.0 parts by vol.

EXAMPLE 17 Suppositories The suppository composition is compounded fromthe following ingredients:

Parts 2,7 dimorpholino 4 diisopropanolamino 6- (p-tolyl)-pteridine 100.0Cocoa butter 1600.0

Total 1700.0

Compounding procedure: The pteridine compound, in finely pulverizedform, is stirred with the aid of an immersion homogenizer into the cocoabutter which had been melted and cooled to about 40 C. The resultingmixture is cooled to 35 C. and is then poured into cooled suppositorymolds holding 1700 mgm. of the mixture. Each suppository contains mgm.of the active ingredient.

Although the above dosage unit composition examples illustrate only onespecific compound of the invention as an active ingredient, it should beunderstood that any of the other compounds embraced by Formula I may besubstituted for the pteridine compound in Examples 13 through 17.Moreover, the amount of active ingredient in these examples may bevaried within the dosage unit range set forth above, and the amounts andnature of the inert carrier ingredients may be varied to meet particularrequirements.

I claim:

1. A pteridine compound of the formula 4. A pteridine compound as inclaim 1, wherein R is fl-hydroxy-n-propyl, R is p-hydroxyethyl, and Aris 2- thienyl.

5. A pteridine compound as in claim 1, wherein R and R arefl-hydroxy-n-propyl, and Ar is Z-thienyl.

References Cited UNITED STATES PATENTS 1,915,334- 6/ 1933 Salzberg eta1. 260243 1 0 2,075,359 3/1937 Salzberg et a1 16722 2,362,614 11/ 1944Calva 16722 2,940,972 6/1960 Roch 260-2475 US. Cl. X.R.

age UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.33753125 Dated October 28 1969 Inventcifls) JOSEF ROCH It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 5, Example '7 Formula N I should read D Q U Signed and sealedthis 17th day of February 1970 (SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM Ii. SCHUYLER, JR. 2

Commissioner of Patents Attesting Officer

